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Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance

Secrier, Maria; Li, Xiaodun; de Silva, Nadeera; Eldridge, Matthew D.; Contino, Gianmarco; Bornschein, Jan; MacRae, Shona; Grehan, Nicola; O'Donovan, Maria; Miremadi, Ahmad; Yang, Tsun-Po; Bower, Lawrence; Chettouh, Hamza; Crawte, Jason; Galeano-Dalmau, Núria; Grabowska, Anna; Saunders, John; Underwood, Tim; Waddell, Nicola; Barbour, Andrew P.; Nutzinger, Barbara; Achilleos, Achilleas; Edwards, Paul A.W.; Lynch, Andy G.; Tavaré, Simon; Fitzgerald, Rebecca C.; Noorani, Ayesha; Elliott, Rachael Fels; Weaver, Jamie; Ross-Innes, Caryn; Smith, Laura; Abdullahi, Zarah; de la Rue, Rachel; Cluroe, Alison; Malhotra, Shalini; Hardwick, Richard; Ford, Hugo; Smith, Mike L.; Davies, Jim; Turkington, Richard; Hayes, Stephen J.; Ang, Yeng; Preston, Shaun R.; Oakes, Sarah; Bagwan, Izhar; Save, Vicki; Skipworth, Richard J.E.; Hupp, Ted R.; O'Neill, J. Robert; Tucker, Olga; Taniere, Philippe; Noble, Fergus; Owsley, Jack; Lovat, Laurence; Haidry, Rehan; Eneh, Victor; Crichton, Charles; Barr, Hugh; Shepherd, Neil; Old, Oliver; Lagergren, Jesper; Gossage, James; Davies, Andrew; Chang, Fuju; Zylstra, Janine; Sanders, Grant; Berrisford, Richard; Harden, Catherine; Bunting, David; Lewis, Mike; Cheong, Ed; Kumar, Bhaskar; Parsons, Simon L.; Soomro, Irshad; Kaye, Philip; Collier, Pamela; Igali, Laszlo; Welch, Ian; Scott, Michael; Sothi, Shamila; Suortamo, Sari; Lishman, Suzy; Beardsmore, Duncan; Francies, Hayley E.; Garnett, Mathew J.; Pearson, John V.; Nones, Katia; Patch, Ann-Marie; Grimmond, Sean M.

Authors

Maria Secrier

Xiaodun Li

Nadeera de Silva

Matthew D. Eldridge

Gianmarco Contino

Jan Bornschein

Shona MacRae

Nicola Grehan

Maria O'Donovan

Ahmad Miremadi

Tsun-Po Yang

Lawrence Bower

Hamza Chettouh

Jason Crawte

Núria Galeano-Dalmau

Anna Grabowska

John Saunders

Tim Underwood

Nicola Waddell

Andrew P. Barbour

Barbara Nutzinger

Achilleas Achilleos

Paul A.W. Edwards

Andy G. Lynch

Simon Tavaré

Rebecca C. Fitzgerald

Ayesha Noorani

Rachael Fels Elliott

Jamie Weaver

Caryn Ross-Innes

Laura Smith

Zarah Abdullahi

Rachel de la Rue

Alison Cluroe

Shalini Malhotra

Richard Hardwick

Hugo Ford

Mike L. Smith

Jim Davies

Richard Turkington

Stephen J. Hayes

Yeng Ang

Shaun R. Preston

Sarah Oakes

Izhar Bagwan

Vicki Save

Richard J.E. Skipworth

Ted R. Hupp

J. Robert O'Neill

Olga Tucker

Philippe Taniere

Fergus Noble

Jack Owsley

Laurence Lovat

Rehan Haidry

Victor Eneh

Charles Crichton

Hugh Barr

Neil Shepherd

Oliver Old

Jesper Lagergren

James Gossage

Andrew Davies

Fuju Chang

Janine Zylstra

Grant Sanders

Richard Berrisford

Catherine Harden

David Bunting

Mike Lewis

Ed Cheong

Bhaskar Kumar

Simon L. Parsons

Irshad Soomro

Philip Kaye

Pamela Collier

Laszlo Igali

Ian Welch

Michael Scott

Shamila Sothi

Sari Suortamo

Suzy Lishman

Duncan Beardsmore

Hayley E. Francies

Mathew J. Garnett

John V. Pearson

Katia Nones

Ann-Marie Patch

Sean M. Grimmond



Abstract

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.

Journal Article Type Article
Publication Date Oct 31, 2016
Journal Nature Genetics
Print ISSN 1061-4036
Electronic ISSN 1546-1718
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 48
Issue 10
APA6 Citation Secrier, M., Li, X., de Silva, N., Eldridge, M. D., Contino, G., Bornschein, J., …Grimmond, S. M. (2016). Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nature Genetics, 48(10), https://doi.org/10.1038/ng.3659
DOI https://doi.org/10.1038/ng.3659
Keywords DNA sequencing, Genetics research, Oesophageal cancer
Publisher URL http://dx.doi.org/10.1038/ng.3659
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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